Clinical Vignette

A 45-year-old previously healthy, Indian male, working as an engineer in the United States returned from India in August after a 6-week stay visiting with his parents. One week after his return, he presented to the emergency ward with 4 days of fever to 102° F, headache, and diarrhea. His facies was flushed; he had mild confusion, severe lethargy, a moderately stiff neck, and a temperature of 39.4° C (103° F). A lumbar puncture demonstrated a normal cerebrospinal fluid (CSF). His peripheral WBC was 12,000/mm³, with a hemoglobin of 10 g and a platelet count of 40,000/mm³. His blood glucose level was 56 mg/dL. A peripheral blood smear demonstrated multiple intraerythrocytic ring forms consistent with the trophozoites of Plasmodium falciparum with a parasite count of 3%.

The patient was treated with intravenous artesunate, obtained from the Centers for Disease Control and Prevention (CDC), and doxycycline. He became afebrile, alert, and oriented after 3 days of intravenous therapy. His oral treatment regimen was completed after 7 days of doxycycline.

Comment: Malaria remains a major cause of morbidity and mortality in the developing world and the most important treatable cause of acute parasitic infection in travelers returning to their Westernized homelands. In the United States, 1564 imported cases were reported during 2006; 39% were attributable to P. falciparum. Immigrants who have recently visited with friends and relatives in their countries of origin often do not take antimalarial prophylaxis and are at higher risk of acquiring malaria.

Malaria continues to have a global presence, primarily affecting individuals living in South and Central America, Africa, and Asia (Fig. 50-1). Close to a half billion individuals are affected annually with up to a million deaths each year. Previously endemic in the United States, public health measures have greatly decreased its incidence here. However, at least a thousand cases are reported annually here and are primarily related to P. falciparum affecting travelers to endemic geographic areas.

Figure 50-1 Geographic Distribution of Malaria.

Epidemiology

Malaria is caused by four common species of parasites: P. falciparum, P. vivax, P. ovale, and P. malariae. Each form is transmitted to the human from the bites of infected Anopheles mosquitoes. Erythrocytes infected with mature parasites of P. falciparum adhere to endothelial cells in the microvasculature of many organs, including the brain, and undergo a complex interplay with host factors, leading to the manifestations of cerebral malaria.

Clinical Features

Cerebral malaria is the most life-threatening form, having an adult mortality rate of 20–50%; this is even worse in children. It is caused by P. falciparum, with rare exceptional instance of P. vivax. Its primary neurologic features range from irritability and confusion to seizures and coma. Early on there are usually several days of fever and other nonspecific symptoms indistinguishable from those of uncomplicated malaria. Patients may gradually develop coma or in contrast deteriorate suddenly and persistently after a generalized seizure. Grand mal convulsions occur in about half of adult patients. The seizures are often exacerbated by hypoglycemia and lactic acidosis metabolic features that often accompany severe malaria. Hypoglycemia is a common and important abnormality in patients with cerebral malaria and may not be suspected clinically because the symptoms (anxiety, restlessness, and tachycardia) are attributed to the infection itself.

Diagnosis

If malaria is suspected, peripheral blood smears need to be examined every 8–24 hours by an experienced microscopist. In a patient with fever and abnormal mental status who was potentially exposed to malaria, antimalarial chemotherapy must be started immediately even if blood smears are repeatedly negative. Microscopic examination and culture of CSF is also essential in patients with cerebral malaria to exclude other treatable central nervous system (CNS) infections.

Therapy

Increased drug resistance has led to combination therapy for malaria. The treatment of cerebral malaria consists of either intravenous quinidine or artesunate accompanied by doxycycline (Fig. 50-2). Intravenous quinidine has to be administered in an ICU setting with electrocardiographic monitoring, as it may lead to severe arrhythmias. Exchange transfusion should be strongly considered for persons with a parasite density of more than 5–10% or even with a lower level of parasitemia if the cerebral malaria is severe or other complications of the malaria occur, including non–volume overload pulmonary edema, or renal complications.

Figure 50-2 Treatment of Malaria.

Clinical Vignette

A 38-year-old West African woman, who migrated from her native country 4 months ago, was evaluated in an emergency department for a few weeks of bizarre behavior. In the preceding months, she noted modest weight loss and progressive failure to thrive. She was referred to an inpatient psychiatric service, where she became more lethargic. Her physical examination revealed a low-grade fever with a suspicion of hepatomegaly but was otherwise normal.

Laboratory tests demonstrated a white cell count of 6400/mm, hemoglobin 10 g, and normal platelets. Her liver function tests revealed a mild transaminitis. A careful exam of her peripheral blood smear showed a trypomastigote. HIV antibody was negative. The patient’s basic CSF parameters were normal. However, both her indirect fluorescent antibody (IFA) and enzyme-linked immunosorbent assay (ELISA) to Trypanosoma gambiense in her CSF were positive. Treatment was started with melarsoprol but was stopped because of progressive encephalopathy. The patient’s family signed her out of the hospital against medical advice and she was lost to follow-up.

Comment: With the world becoming “smaller,” previously “exotic” infectious diseases may now be seen anywhere, including economically highly developed countries. Cultural issues also arise, as well illustrated here, where the family made a decision not to allow attempts at a second line of therapy such as intravenous eflornithine when the first medication trial was not successful.

Epidemiology

After being brought under control for many years, ever since the 1970s, African trypanosomiasis has reemerged, as a new epidemic of enormous proportions. This disease is divided into two different forms, each characterized by meningoencephalitis when it reaches more advanced stages. Both are transmitted by the bites of infected tsetse flies.

Clinical Features

West African sleeping sickness accounts for more than 90% of reported cases of sleeping sickness and causes a chronic infection primarily occurring in west and central Africa. It is caused by Trypanosoma brucei gambiense. Individuals can be infected for months or even years without experiencing any major symptoms or signs. Initially, the systemic disease presents with fever, fatigue, weight loss, cervical lymphadenopathy and hepatosplenomegaly.

Once the neurologic manifestations emerge, the patient often has developed an advanced stage of central nervous system (CNS) infection. Personality changes are common; patients are frequently mistaken as having psychiatric disorders, as in this case. In the early phases of CNS disease, a disruption of the normal circadian sleep rhythm occurs (Fig. 50-3).

Figure 50-3 Trypanosomiasis (African Sleeping Sickness).

East African trypanosomiasis, caused by Trypanosome brucei rhodesiense, causes a more acute infection in contrast to the more chronic West African form. Neurologic symptoms develop rapidly after just a few months or weeks.

Diagnosis

An African sleeping sickness diagnosis is not an easy one to establish in the early phases of the disease when there may not be any CSF changes. Patients are classified as early- or late-stage disease based on CSF findings: those with a CSF WBC >5/mm, often with mild lymphocytic pleocytosis (rarely above 400/mL) and an increased protein content accompanied by a high level of IGM or with trypanosomes demonstrated in CSF seen, are in late-stage disease. Electroencephalography (EEG) can aid in the diagnosis by demonstrating the characteristic impairment in vigilance.

Although visualization of the trypanosome on peripheral smear is the gold standard for diagnosis, immunological tests such as the ELISA and IFA for antibody levels in the CSF are relatively sensitive and specific for the diagnosis of West African trypanosomiasis. However, no reliable serologic tests for East African trypanosomiasis are currently available for practical diagnostic use.

Therapy

Treatment of African trypanosomiasis is handicapped by the lack of effective nontoxic drugs. Drugs used for early-stage T. rhodesiense infection, such as suramin, do not cross the blood–brain barrier. Therefore the risk of disease progression to the neurologic stage exists despite therapy of earlier disease. The most widely used drug is melarsoprol; this is highly toxic because of its own predisposition to cause a toxic encephalopathy. There are also reports of high relapse rates with standard treatment with melarsoprol.

Intravenous eflornithine is an alternative, less toxic drug recommended in areas where the resistance to melarsoprol is greater than 15%. However, it is more expensive and more difficult to administer because it requires longer intravenous injection as opposed to melarsoprol, which requires five intramuscular injections. However concerns about the development of resistance to monotherapy have prompted clinical trials using combination eflornithine and nifurtimox. Other drugs such as suramin do not cross the blood–brain barrier, and therefore the risk of progression of the disease to the neurologic stage exists despite therapy of earlier disease.

Clinical Vignette

A 29-year-old Asian man, a native Chinese previously living in northern India before he immigrated to the United States 10 years ago, presented to the emergency department after having several witnessed tonic-clonic seizures. He had complained of intermittent mild headaches over the prior week and had no significant past medical history.

On presentation he was postictal; his temperature was 38.5° C (101.3° F). His right pupil was minimally larger than the left, and there was no papilledema. He was intubated during a subsequent seizure for airway protection.

Brain CT revealed a single hypodense area lateral to the right lateral ventricle. Spinal fluid analysis indicated normal results, including a negative Gram stain. Plain radiographs of his extremities showed multiple small calcific densities in the soft tissues, and a serum cysticercosis immunoblot was positive. He was treated with albendazole and dexamethasone, and his seizures resolved.

Epidemiology

Cysticercosis is a relatively common cause of seizure disorders, particularly in individuals from Central and South America, including those who have immigrated to the United States. It may occur in both immunocompromised and nonimmunocompromised individuals. It results from infection with the larval form of the porcine tapeworm Taenia solium. Humans acquire the adult tapeworm by eating undercooked pork and become infected with the larval stage (cysticercus) by ingesting tapeworm eggs. Eggs hatch within the small intestine, burrow into venules, and are carried to distant sites, including the CNS and muscle. Because the larvae are relatively large, they may lodge in the subarachnoid space, ventricles, or brain tissue (Fig. 50-4).

Figure 50-4 Cysticerosis.

Clinical Presentation

Symptoms may not occur for 4–5 years, when larvae die and provoke an inflammatory response. Cysts within the cerebrum may mimic brain tumors, leading to a variety of focal symptoms. Intra-ventricular cysts may lead to CSF obstruction with signs of hydrocephalus. On other occasions, subarachnoid space cysts may lead to symptoms of a chronic meningitis and arachnoiditis.

Diagnosis

Old nonviable cysts eventually calcify, simplifying detection. MRI or contrast-enhanced CT may reveal signs of CNS infection. Serum or CSF serologic study and biopsy of subcutaneous cysts or skeletal muscle calcifications support the diagnosis.

Therapy

Albendazole or praziquantel are the therapies of choice for cysticercosis. Steroids are used to decrease inflammation. Traditional anticonvulsants are indicated to control seizures.

Epidemiology

The lifetime risk of developing systemic sarcoidosis is 2.4% in the African-American population, almost three times greater than Caucasians, who have a 0.85% lifetime likelihood of developing this disorder. This is a relatively benign disorder overall, and as many as 66.7% of patients eventually diagnosed with sarcoidosis are asymptomatic. Often this is discovered on a routine chest radiograph identifying hilar adenopathy. NS per se is much less common, perhaps having an incidence of 5–15% of patients diagnosed.

Clinical Presentation

This depends on the propensity of NS to primarily infiltrate the meninges with inflammatory cells leading to a pachymeningitis and thus producing various cranial nerve palsies, particularly the optic, trigeminal, facial and auditory nerves. When there is extension of this process along Virchow–Robin spaces, there is a predilection for involvement of the hypothalamus pituitary axis, the third ventricle, and eventually brain parenchymal involvement. Early on, hypogonadism or hypothyroidism are frequent presentations. On occasion, lower bulbar, cerebellar, or spinal cord involvement occurs. The peripheral motor sensory unit may also be affected with granulomas, and mononuclear cells developing in the epineurium, perineurium, and endoneurium often in an asymmetric fashion leading to a cauda equina syndrome or a mononeuritis multiplex. Various degrees of a myopathy may occur.

Systemic signs that often provide clues to the diagnosis of NS include erythema nodosum, uveitis, and hepatomegaly.

Diagnosis

A definitive diagnosis requires a tissue specimen, most typically a hilar node biopsy as illustrated by the above vignette. Often one can gain supportive clues from a cranial MRI, particularly with its high sensitivity especially involving the leptomeninges. However, this has a low specificity, as it may mimic MS in its propensity for some white matter involvement. At other times, MRI may demonstrate lesions mimicking a tumor (Fig. 50-6). The CSF is abnormal in 80% of NS patients, not only a cellular response but also an elevated ACE, something that may only be positive here rather than the serum. Chest radiographs are positive in more than half of the patients. Chest CT is sometimes positive when routine chest radiographs are normal. Lastly an otherwise unexplained hypercalcemia as well as abnormal liver function tests may also give further hint that NS is present.

Figure 50-6 Neurosarcoidosis: MRI and Pathology.

Therapy

Corticosteroids are the cornerstone of therapy. In general, they are very effective, either commencing orally with 20–60 mg daily or intravenously with methylprednisolone. There are no randomized trials. MRI is helpful in gauging potential therapeutic responses. The best results often occur in patients with cranial or peripheral nerve presentation. The presence of MRI enhancement suggests the presence of active inflammation with good prognosis with corticosteroids, whereas lack of the same may be compatible with fibrosis and chronicity and thus a lesser chance of a good therapeutic response.

A prime problem is the tendency for relapses to occur during tapering. There is no good data for the various steroid-sparing agents such as methotrexate, azathioprine, and mycophenolate.

Clinical Vignette

A 30-year-old, right-handed male insurance agent was evaluated for intermittent twitching of his right hand for 3 months. The patient was currently in good health; however, 3 years earlier he experienced an episode of disseminated histoplasmosis when he was working in Ohio trapping rodents in the outdoors. He was treated with itraconazole for 9 months, with apparent cure of his disease. On a recent routine medical examination, a mild neutropenia with a WBC count of 2800/mm and borderline thrombocytopenia were noted. A bone marrow biopsy revealed rare granulomas but negative culture for H. capsulatum.

Neurologic examination demonstrated a slight intention tremor of his right hand with difficulty writing. His general physical examination was completely normal. Brain MRI revealed two brain abscesses: a large one in the cerebellum causing a mild midline shift and another in the right frontal cerebral cortex. His urine Histoplasma antigen was positive at 4.6 ELISA units. HIV antibody was negative.

He underwent a biopsy and debulking of his cerebellar lesion, and the fungal smear showed many yeast forms of Histoplasma. The patient was treated for twelve months with voriconazole. He responded well with a rapid normalization in his urinary Histoplasma antigen; however he had a persistent neutropenia.

Epidemiology

In the United States, histoplasmosis is primarily acquired in the endemic areas of the Ohio and Mississippi river valleys. This occurs from the inhalation of spores of H. capsulatum found in the soil contaminated by fecal material from chickens, starlings, and bats. Travelers to other countries where histoplasmosis is also found have acquired it after exposure in caves inhabited by infected bats or from inhalation from spores found in the soil. Most infections are asymptomatic, but symptomatic disease may occur even in the normal host. Disseminated disease tends to occur in infants, the elderly, and patients with hematologic malignancies and HIV infection (where disseminated disease is usually diagnosed in patients with CD4 counts less than 200 cells/mm³).

CNS histoplasmosis is a manifestation of disseminated disease and is uncommon in North America. It mimics tuberculosis with parenchymal involvement occurring as single or multiple focal granulomas (Fig. 50-7). Granulomatous basilar meningitis may also occur. Abscess formation is rare except in immunocompromised hosts. Patients usually present with signs and symptoms of subacute meningitis with fever, stiff neck, and photophobia. Focal neurologic deficits are more common in CNS histoplasmosis than either cryptococcosis or coccidioidomycosis.

Figure 50-7 Histoplasmosis.

Diagnosis

Isolation of H. capsulatum is difficult from the CSF; cultures of bone marrow, blood, and urine are more likely to be positive. The more rapid detection of Histoplasma antigen in blood, urine, or CSF is often diagnostic of disseminated histoplasmosis and can be followed to negativity with antifungal therapy. A false-positive test for serum Histoplasma antigen may be present in disseminated coccidioidomycosis.

Therapy

There is no clearly defined therapy that is most effective for CNS histoplasmosis. Initial therapy with liposomal amphotericin followed by itraconazole for at least 1 year is suggested. High rates of relapse of up to 40% occur with shorter periods of therapy. The newer azoles, such as voriconazole and posaconazole, are also effective in vitro and may obviate the unreliable blood levels achieved by itraconazole. HIV-positive patients with histoplasmosis need to stay on suppressive itraconazole therapy unless their CD4 count exceeds 150 cells/mm³.

Clinical Vignette

A 68-year-old California woman developed intermittent fever, weight loss, and occasional confusion a few months after a trip around the world that included traveling to West Africa and Brazil. She subsequently had headache and stiff neck and saw her local doctor, who found her with a temperature of 37.7° C (99.8° F), minimally confused but no meningismus, that is, a stiff neck. There were no other significant physical findings.

Chest radiograph revealed mediastinal lymphadenopathy with some fibrosis in the right upper lobe. Her PPD was negative. A lumbar puncture demonstrated a CSF WBC count of 112/mm³, a protein of 80 mg/dL, and glucose of 45 mg/dL. Brain MRI showed basilar meningitis. Her complement fixation titer to C. immitis was 1 : 8 in the CSF. Her CSF culture did not grow any fungal organisms.

She was started on 800 mg of intravenous fluconazole and intrathecal amphotericin. Mild right-sided hydrocephalus developed but it did not progress with continued therapy. Her symptoms cleared over the next several months with improvement of her MRI. She completed a course of 6 months of intrathecal amphotericin until her CSF parameters normalized and her complement fixation titer became negative. She is being continued on 400 mg of oral fluconazole. It is anticipated that because of her advanced age, she would require this drug lifelong.

Epidemiology

C. immitis is found in soil only in the Western Hemisphere, particularly in the southwestern United States, the northern Pacific coast of Mexico, Guatemala, Honduras, and Venezuela. Aerosolized arthroconidia are inhaled and frequently infect individuals asymptomatically in endemic areas. About 0.5% of exposed patients will develop disseminated disease via lymphatic or vascular spread to the skin, bone, meninges, and genitourinary tract. CNS involvement develops in 33–50% of patients with disseminated disease. Sometimes the neuraxis is the only site of symptomatic disease. Risk factors for dissemination include older age, pregnancy, and immunosuppression (including HIV infection).

Clinical Features

When there is central nervous system involvement, this infection causes a subacute to chronic meningitis with a predilection for the basilar meninges. Here a progressive fibrosing granulomatous reaction occurs. This may result in hydrocephalus that eventually requires shunting. Focal space-occupying lesions are rare. C. immitis is recovered in CSF in only 50% of patients with known meningitis.

Diagnosis

Confirmation of the presence of coccidiomycosis is presumptively made in patients with chronic meningitis if the complement fixing antibody to C. immitis is positive in the CSF and any titer or the serum complement fixation titer to C. immitis is positive at 1 : 16.

Therapy

Treatment with high-dose fluconazole (400–800 mg/day) in uncomplicated cases is preferred by many physicians. In patients with high antibody titers in the CSF or who are immunosuppressed, this is often best accompanied by intrathecal administration of amphotericin. Patients who respond to oral fluconazole should probably continue on this regimen indefinitely. Those who do not respond initially to the azoles should be started on intrathecal amphotericin. Central nervous system vasculitis is another complication of coccidioidal meningitis. This may respond to the addition of high-dose steroids.